Inflammation in the body occurs in response to numerous conditions including, for example, physical injury, allergy, tumor growth, certain disease states, chemical damage and microbial infection. Representative of local effects that can occur are increased vascular permeability, release of degradative enzymes, migration to the affected site by leukocytes, neutrophil burst response to destroy invading cells and secretion of cytokines. There is considerable interest in the development of therapeutic compounds and compositions capable of controlling inflammation.
Psoriasis is a common chronic inflammatory and proliferative skin disease, characterized by increased cell proliferation at affected sites. At the molecular level, psoriasis is characterized by an abnormal metabolism of an arachidonic acid, particularly in the lipoxygenase pathways. Lesional skin contains increased functional responses of neutrophils. See, for example, Bedord, et al., J. Invest. Dermatol, 85:30 (1983); Schroder, et al., J. Invest. Dermatol, 85:30 (1985); and Schroeder, J. M., Invest. Dermatol., 86:331 (1986). However, anthralin therapy is associated with several unpleasant side effects including increased inflammation and irritation of non-effected skin surrounding treated lesions.
There is substantial evidence that generation of free radicals (Finnen, M. J., Lancet II, 1129-1130 (1984) and, Shroot, et al., Arzneim.-Forsch./Drug Res., 36:1253-1255 (1986)) and active oxygen species (Muller, et al., Arch Pharm (Weinheim), 320: 59-66 (1987); Muller, et al., Biochem. Pharmacol., 37:4277-4280 (1988); Muller, et al., Biochem. Pharmacol, 46:1695-1704 (1993); and Muller et al., Arzneim-Forsch/Drug Res., 41:1176-1181 (1991)) play a key role in both the activity and side effects caused by anthralin.
Anthralin has been demonstrated to produce superoxide radicals by one electron reduction of oxygen (Muller, et al., Arch. Pharm. (Weinheim, Ger.), 320: 59-66 (1987)). There is evidence that iron plays a significant role in superoxide radical production by antipsoriatic anthrones in vivo. The significant production of superoxide radicals requires the presence of a transition metal, such as iron, since the direct reaction of oxygen with biomolecules is spin forbidden (Miller, et al., Free Radical Biol. Med, 8: 95-108 (1990)). Moreover, superoxide radicals readily undergo dismutation to form hydrogen peroxide and oxygen, which have only moderate reactivity and therefore, cannot be responsible for the biological damage observed in systems in which they are generated (Fridovich, I., Arch. Biochem. Biophys., 247:1-11 (1986)). It has been suggested, therefore, that the observed biological damage is due to the formation of hydroxyl radicals (Halliwell, et al., Methods Enzymol., 186:1-85 (1990)), which may be catalyzed by ferrous iron via the Haber-Weiss cycle, a superoxide-driven Fenton reaction (Gutteridge, et al., Biochem. J., 199:268-265 (1981). Morever, iron has been demonstrated to play a key role in the formation of hydroxyl radicals by anthralin (Muller, et al., Biochem. Pharmacol; 37:4277-4280 (1988); Muller, et al., Biochem. Pharmacol, 46:1695-1704 (1993)) and has been suggested to be the most likely candidate for catalyzing hydroxyl radical generation in vivo (Halliwell, et al., Methods Enzymol., 186:1-85 (1990)). biological damage is due to the formation of hydroxyl radicals (Halliwell, et al., Methods Enzymol., 186:1-85 (1990)), which may be catalyzed by ferrous iron via the Haber-Weiss cycle, a superoxide-driven Fenton reaction (Gutteridge, et al., Biochem. J., 199:268-265 (1981). Morever, iron has been demonstrated to play a key role in the formation of hydroxyl radicals by anthralin (Muller, et al., Biochem. Pharmacol; 37:4277-4280 (1988); Muller, et al., Biochem. Pharmacol, 46:1695-1704 (1993)) and has been suggested to be the most likely candidate for catalyzing hydroxyl radical generation in vivo (Halliwell, et al., Methods Enzymol., 186:1-85 (1990)).
Further evidence in support of the role of iron in catalyzing superoxide formation includes documentation of enhancement of anthralin-induced lipid peroxidation in the presence of iron (Muller, et al., Biochem. Pharmacol., 46:1695-1704 (1993)), suggesting that iron mediates oxidative damage caused by anthralin and other anti-psoriatic anthrones. Moreover, iron is excreted by skin cells and the level of iron excretion increases at the site of psoriatic lesions (Trenam, et al., J. Invest., Dermatol., 99:674-682 (1992)).
It has been proposed that administration of 5-lypoxygenase inhibitors may be therapeutically useful for treatment of inflammatory conditions, including psoriasis. However, some inflammatory conditions, such as psoriasis involve both inflammatory and hyperproliferative process. Consequently, compounds that are targeted toward only one aspect of the disease are unlikely to be totally beneficial. There exists, therefore, a need for anti-inflammatory agents capable of inhibiting lipoxygenase pathways of arachidonic acid metabolism to thereby inhibit the proliferative activity of the products of lipoxgenase pathways e.g., 5-HETE and LTB.sub.4, while simultaneously suppressing iron-dependent generation of oxygen radicals.